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Camptothecin (CPT) and etoposide (ETP) trap topoisomerase-DNA covalent intermediates, resulting in formation of DNA damage that can be cytotoxic if unrepaired. CPT and ETP are prototypes for molecules widely used in chemotherapy of cancer, so defining the mechanisms for repair of damage induced by treatment with these compounds is of great interest. In  S. cerevisiae , deficiency in  MRE11 , which encodes a highly conserved factor, greatly enhances sensitivity to treatment with CPT or ETP. This has been thought to reflect the importance of double-strand break (DSB) repair pathways in the response to these to agents. Here we report that an  S. cerevisiae  strain expressing the  mre11-H59A  allele, mutant at a conserved active site histidine, is sensitive to hydroxyurea and also to ionizing radiation, which induces DSBs, but not to CPT or ETP. We show that  TDP1 , which encodes a tyrosyl-DNA phosphodiesterase activity able to release both 5′- and 3′-covalent topoisomerase-DNA complexes  in vitro , contributes to ETP-resistance but not CPT-resistance in the  mre11-H59A  background. We further show that CPT- and ETP-resistance mediated by  MRE11  is independent of  SAE2 , and thus independent of the coordinated functions of  MRE11  and  SAE2  in homology-directed repair and removal of Spo11 from DNA ends in meiosis. These results identify a function for  MRE11  in the response to topoisomerase poisons that is distinct from its functions in DSB repair or meiotic DNA processing. They also establish that cellular proficiency in repair of DSBs may not correlate with resistance to topoisomerase poisons, a finding with potential implications for stratification of tumors with specific DNA repair deficiencies for treatment with these compounds.

MRE11 Function in Response to Topoisomerase Poisons Is Independent of its Function in Double-Strand Break Repair in Saccharomyces cerevisiae